Ribaxamase, an orally administered β-lactamase, protects the gut microbiome in patients treated with ceftriaxone (original) (raw)
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Infection and Drug Resistance
Introduction: Intravenous (IV) β-lactam antibiotics, excreted through bile into the gastrointestinal (GI) tract, may disrupt the gut microbiome by eliminating the colonization resistance from beneficial bacteria. This increases the risk for Clostridium difficile infection (CDI) and can promote antimicrobial resistance by selecting resistant organisms and eliminating competition by non-resistant organisms. Ribaxamase is an orally administered β-lactamase for use with IV βlactam antibiotics (penicillins and cephalosporins) and is intended to degrade excess antibiotics in the upper GI before they can disrupt the gut microbiome and alter the resistome. Methods: Longitudinal fecal samples (349) were collected from patients who participated in a previous Phase 2b clinical study with ribaxamase for prevention of CDI. In that previous study, patients were treated with ceftriaxone for a lower respiratory tract infection and received concurrent ribaxamase or placebo. Extracted fecal DNA from the samples was subjected to whole-genome shotgun sequencing and analyzed for the presence of antimicrobial resistance (AMR) genes by alignment of sequences against the Comprehensive Antibiotic Resistance Database. A qPCR assay was also used to confirm some of the results. Results: Database alignment identified~1300 acquired AMR genes and gene variants, including those encoding β-lactamases and vancomycin resistance which were significantly increased in placebo vs ribaxamase-treated patients following antibiotic exposure. qPCR corroborated the presence of these genes and supported both new acquisition and expansion of existing gene pools based on no detectable copy number or a low copy number in preantibiotic samples which increased post-antibiotics. Additional statistical analyses demonstrated significant correlations between changes in the gut resistome and clinical study parameters including study drug assignment and β-lactamase and vancomycin resistance gene frequency. Discussion: These findings demonstrated that ribaxamase reduced changes to the gut resistome subsequent to ceftriaxone administration and may help limit the emergence of AMR.
Antimicrobial agents and chemotherapy, 2017
SYN-004 (ribaxamase) is a β-lactamase designed to be orally administered concurrently with intravenous β-lactam antibiotics, including most penicillins and cephalosporins. Ribaxamase's anticipated mechanism of action is to degrade excess β-lactam antibiotic that is excreted into the small intestine. This enzymatic inactivation of excreted antibiotic is expected to protect the gut microbiome from disruption and thus prevent undesirable side effects, including secondary infections such as Clostridium difficile infections, as well as other antibiotic-associated diarrheas. In phase 1 clinical studies, ribaxamase was well tolerated compared to a placebo group and displayed negligible systemic absorption. The two phase 2a clinical studies described here were performed to confirm the mechanism of action of ribaxamase, degradation of β-lactam antibiotics in the human intestine, and were therefore conducted in subjects with functioning ileostomies to allow serial sampling of their intest...
The gut microbiome, composed of the microflora that inhabit the gastrointestinal tract and their ge-nomes, make up a complex ecosystem that can be disrupted by antibiotic use. The ensuing dysbiosis is conducive to the emergence of opportunistic pathogens such as Clostridium difficile. A novel approach to protect the microbiome from antibiotic-mediated dysbiosis is the use of beta-lactamase enzymes to degrade residual antibiotics in the gastrointestinal tract before the microflora are harmed. Here we present the preclinical development and early clinical studies of the beta-lactamase enzymes, P3A, currently referred to as SYN-004, and its precursor, P1A. Both P1A and SYN-004 were designed as orally-delivered, non-systemically available therapeutics for use with intravenous beta-lactam antibiotics. SYN-004 was engineered from P1A, a beta-lactamase isolated from Bacillus licheniformis, to broaden its antibiotic degradation profile. SYN-004 efficiently hydrolyses penicillins and cephalosporins, the most widely used IV beta-lactam antibiotics. In animal studies, SYN-004 degraded ceftriaxone in the GI tract of dogs and protected the microbiome of pigs from ceftriaxone-induced changes. Phase I clinical studies demonstrated SYN-004 safety and tolerability. Phase 2 studies are in progress to assess the utility of SYN-004 for the prevention of antibiotic-associated diarrhea and Clostridium difficile disease.
Oral Beta-Lactamase Protects the Canine Gut Microbiome from Oral Amoxicillin-Mediated Damage
Microorganisms
Antibiotics damage the gut microbiome, which can result in overgrowth of pathogenic microorganisms and emergence of antibiotic resistance. Inactivation of antibiotics in the small intestine represents a novel strategy to protect the colonic microbiota. SYN-004 (ribaxamase) is a beta-lactamase formulated for oral delivery intended to degrade intravenously administered beta-lactam antibiotics in the gastrointestinal (GI) tract. The enteric coating of ribaxamase protects the enzyme from stomach acid and mediates pH-dependent release in the upper small intestine, the site of antibiotic biliary excretion. Clinical benefit was established in animal and human studies in which ribaxamase was shown to degrade ceftriaxone in the GI tract, thereby preserving the gut microbiome, significantly reducing Clostridioides difficile disease, and attenuating antibiotic resistance. To expand ribaxamase utility to oral beta-lactams, delayed release formulations of ribaxamase, SYN-007, were engineered to ...
Computational and Structural Biotechnology Journal, 2021
Background: The globally increasing resistance due to extended-spectrum beta-lactamase producing Enterobacteriaceae is a major concern. The objective of this work was to develop a murine model to study the gut bacteria parameters during complex antibiotics like cefotaxime and ceftriaxone treatment and to compare the fecal carriage of ESBL-producing Enterobacteriaceae. Methods: SWISS mice were treated either with ceftriaxone or with cefotaxime or with NaCl 0.9% as a control group from day 1 to day 5. We performed a gavage at day 4 with a Klebsiella pneumonia CTX-M9. We collected stools and performed pharmacological measurements, cultures and 16S rRNA gene amplification and sequencing during the 12 days of the stool collection. Results: Mice treated with ceftriaxone were more colonized than mice treated with cefotaxime after gavage (p-value = 0.008; Kruskal-Wallis test). Ceftriaxone and cefotaxime were both excreted in large quantity in gut lumen but they drove architecture of the gut microbiota in different trajectories. Highest levels of colonization were associated with particular microbiota composition using principal coordinate analysis (PCoA) which were more often achieved in ceftriaxone-treated mice and which were preceded by highest fecal antibiotics concentrations in both cefotaxime or ceftriaxone groups. Using LEfSe, we found that twelve taxa were significantly different between cefotaxime and ceftriaxone-treated mice. Using SplinectomeR, we found that relative abundances of Klebsiella were significantly higher in CRO than in CTX-treated mice (p-value = 0.01). Conclusion: Ceftriaxone selects a particular microbial community and its substitution for cefotaxime could prevent the selection of extended-spectrum beta-lactamase producing Enterobacteriaceae.
Microorganisms
Beta-lactamases, enzymes produced by bacteria to degrade beta-lactam antibiotics, have been harnessed as therapeutics to protect the gut microbiome from damage caused by antibiotics. Proof-of-concept of this approach using SYN-004 (ribaxamase), a beta-lactamase formulated for oral delivery with intravenous (IV) penicillins and cephalosporins, was demonstrated with animal models and in humans. Ribaxamase degraded ceftriaxone in the gastrointestinal tract, protected the gut microbiome, significantly reduced the incidence of Clostridioides difficile disease and attenuated emergence of antibiotic resistant organisms. SYN-007 is a delayed release formulation of ribaxamase intended for use with oral beta-lactams. In dogs treated with oral amoxicillin, SYN-007 diminished antibiotic-mediated microbiome disruption and reduced the emergence of antibiotic resistance without altering amoxicillin systemic absorption. Here, SYN-007 function in the presence of clavulanate, a beta-lactamase inhibit...
Clinical drug investigation, 2016
SYN-004 is an orally administered β-lactamase enzyme, designed to be given concurrently with certain intravenous β-lactam antibiotics like cephalosporins. SYN-004 is intended to degrade residual antibiotics excreted into the intestine as a result of hepatobiliary excretion and to prevent the disruption of the gut microbiome by these excess antibiotics. Preserving the gut microbiome is expected to prevent secondary infections by pathogens like Clostridium difficile and protect against other antibiotic-associated diarrheas. Two, randomized, double blind, placebo-controlled Phase 1 clinical studies were conducted in normal healthy adult volunteers to assess the tolerability and systemic absorption of single and multiple doses of SYN-004. A single-ascending dose study investigated single oral doses of 75-750 mg SYN-004 and was conducted in 40 subjects (five cohorts of six active and two placebo subjects). A multiple-ascending dose study investigated doses of 75-300 mg SYN-004, administe...
Antimicrobial agents and chemotherapy, 2014
Antibiotics that are excreted into the intestinal tract may disrupt the indigenous intestinal microbiota and promote colonization by health care-associated pathogens. β-Lactam, or penicillin-type, antibiotics are among the most widely utilized antibiotics worldwide and may also adversely affect the microbiota. Many bacteria are capable, however, of producing β-lactamase enzymes that inactivate β-lactam antibiotics. We hypothesized that prior establishment of intestinal colonization with a β-lactamase-producing anaerobe might prevent these adverse effects of β-lactam antibiotics, by inactivating the portion of antibiotic that is excreted into the intestinal tract. Here, mice with a previously abolished microbiota received either oral normal saline or an oral cephalosporinase-producing strain of Bacteroides thetaiotaomicron for 3 days. Mice then received 3 days of subcutaneous ceftriaxone, followed by either oral administration of vancomycin-resistant Enterococcus (VRE) or sacrifice a...
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2018
Despite advancements, recurrent Clostridium difficile infections (CDI) remain an urgent public health threat with insufficient response rates to currently-approved antibiotic therapies. Microbiota-based treatments appear effective, but rigorous clinical trials are required to optimize dosing strategies and substantiate long-term safety. This randomized, double-blind, placebo-controlled Phase 2B trial (NCT02299570) enrolled adult patients with two or more CDI recurrences to receive: two doses of RBX2660, a standardized microbiota-based drug (Group A); two doses of placebo (Group B); or one dose of RBX2660 followed by one dose of placebo (Group C). Efficacy was defined as prevention of rCDI for 8 weeks following treatment. Participants who recurred within 8 weeks were eligible to receive up to two open-label RBX2660 doses. The primary endpoint was efficacy for Group A compared to Group B. Secondary endpoints included the efficacy of Group C compared to Group B, combined efficacy in th...
Gut Check Time: Antibiotic Delivery Strategies to Reduce Antimicrobial Resistance
Trends in Biotechnology, 2020
Antimicrobial resistance (AMR) has developed into a huge threat to global health, and reducing it is an urgent priority for public health authorities. The importance of a healthy and balanced gut microbiome has been identified as a key protective factor against AMR development, but this can be significantly affected by antibiotic therapy, resulting in dysbiosis and reduction of taxonomic richness. The way in which antibiotics are administered could form an important part of future antimicrobial stewardship strategies, where drug delivery is ideally placed to play a key role in the fight against AMR. This review focuses on drug delivery strategies for antibiotic administration, including avoidance of the gut microbiome and targeted delivery approaches, which may reduce AMR. Resistance and the Gut Microbiome Since the widespread use of antibiotics began in the 1940s, associated antimicrobial resistance (AMR; see Glossary) has proved to problematic, resulting in much mortality and morbidity [1]. AMR has developed into a huge threat to global health, and reducing it is an urgent priority for public health authorities [2]. The importance of a healthy and broad gut microbiome has been identified as a key protective factor against the development of AMR by providing colonization resistance to its host [3,4]. Changes in taxonomic composition are associated with enhanced susceptibility to several conditions including diabetes, obesity, liver, disease, colon cancer, and inflammatory bowel disease (IBD) [5-7]. Antibiotic therapy has a significant impact on the composition of the gut microbiome, causing a considerable reduction in the taxonomic richness and diversity of the microbiota [8,9]. The loss of diversity caused by antibiotic exposure can lead to the establishment of chronic infections, as is the case with Clostridium difficile and vancomycin-resistant enterococci (VRE), and intestinal colonization of the latter is known to precede bloodstream infections in susceptible individuals [10-13]. Dysbiosis in the gut microbiome following antibiotic therapy has been implicated in a myriad of conditions in neonates and preterm infants, including asthma, allergy, obesity, atopy, and issues with brain development [14,15]. The gut has also been highlighted as a major reservoir for antimicrobial resistance genes (ARGs), which can be passed on in the feces, further enhancing the antibiotic resistome of other environments [16-18]. Geographical differences in the antibiotic resistomes of fecal material further strengthen the correlation between antibiotic use and the emergence of resistance via the gut. ARG profiles from different countries correlate with the consumption of antibiotics in those areas, both in terms of antibiotic class and volume of antibiotic used. More ARGs were found for antibiotics that have been in clinical use for a longer period, as well as for those used in animals, such as tetracycline and the cephalosporins [16,19].